Since the early 1940's penicillins, and more recently cephalosporins, have been utilized in man's fight against bacterial infections. These two classes of molecules were the first effective treatments for life threatening infections. Over the past 50 years a tremendous effort has been expended by the scientific community to develop increasingly effective forms of these antibiotics. This effort has led to the identification of specific molecules of great importance to the global medical community. Cefaclor and cephalexin are two examples of cephalosporin antibiotics that have been developed through this process. Despite years of continuing research on new antibiotics, many penicillins and cephalosporins are still widely utilized in the every day fight against pathogenic bacteria.
The primary drawbacks associated with cephalosporins relate to the difficulty and expense of their synthetic production. Several of these important compounds are derived through the synthetic transformation of a penicillin substrate which is itself acquired through a fermentation process. Many steps in the conversion of penicillins to cephalosporins are typically performed using reagents which pose a number of health and environmental risks. In addition, these reagents present economic disadvantages of high outright cost as well as a high cost associated with disposal of the generated waste. These factors significantly affect the overall cost of producing cephalosporin antibiotics.
The present invention relates to novel processes for the preparation of 3-methylenecephams. The present invention utilizes specific catalysts and novel intermediates which have a number of advantages over the analogous procedures known in the art. These catalysts are typically utilized in a less than stoichiometric amount, which may also be recovered and reused, thereby allowing for lower material costs as well as significantly lower waste disposal costs. These two important features combine to lower the overall production cost of 3-methylenecephams and some novel starting materials even eliminate the need for catalysts at all. More specifically, the present invention relates in part to the intramolecular cyclization of penicillin sulfoxide derived monocyclic azetidinone derivatives either thermally or with metal salt catalysts.